Elevation of Pro-Inflammatory Cytokine Levels Following Intra-Articular Fractures—A Systematic Review

Introduction: Intra-articular fractures are a major cause of post-traumatic osteoarthritis (PTOA). Despite adequate surgical treatment, the long-term risk for PTOA is high. Previous studies reported that joint injuries initiate an inflammatory cascade characterized by an elevation of synovial pro-inflammatory cytokines, which can lead to cartilage degradation and PTOA development. This review summarizes the literature on the post-injury regulation of pro-inflammatory cytokines and the markers of cartilage destruction in patients suffering from intra-articular fractures. Methods: We searched Medline, Embase, and Cochrane databases (1960–February 2020) and included studies that were performed on human participants, and we included control groups. Two investigators assessed the quality of the included studies using Covidence and the Newcastle–Ottawa Scale. Results: Based on the surveyed literature, several synovial pro-inflammatory cytokines, including interleukins (IL)-1β, IL-2, IL-6, IL-8, IL-12p70, interferon-y, and tumor necrosis factor-α, were significantly elevated in patients suffering from intra-articular fractures compared to the control groups. A simultaneous elevation of anti-inflammatory cytokines such as IL-10 and IL-1RA was also observed. In contrast, IL-13, CTX-II, and aggrecan concentrations did not differ significantly between the compared cohorts. Conclusions: Overall, intra-articular fractures are associated with an increase in inflammation-related synovial cytokines. However, more standardized studies which focus on the ratio of pro- and anti-inflammatory cytokines at different time points are needed.

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Elevation of Pro-Inflammatory Cytokine Levels Following Intra-Articular Fractures - A Systematic Review

10.20944/preprints202103.0383.v1 ◽

2021 ◽

Author(s):

That Minh Pham ◽

Julie Ladeby Erichsen ◽

Justyna Magdalena Kowal ◽

Søren Overgaard ◽

Hagen Schmal

Keyword(s):

Inflammatory Cytokines ◽

Cartilage Degradation ◽

Cartilage Destruction ◽

Post Injury ◽

Articular Fractures ◽

Cytokine Levels ◽

Newcastle Ottawa Scale ◽

Anti Inflammatory ◽

Human Participants ◽

Pro Inflammatory Cytokines

Intra-articular fractures are a major cause of post-traumatic osteoarthritis (PTOA). Despite adequate surgical treatment, the long-term risk for PTOA is high. Previous studies reported that joint injuries initiate an inflammatory cascade characterized by elevation of synovial pro-inflammatory cytokines, which can lead to cartilage degradation and PTOA development. This review summarizes the literature on the post-injury regulation of pro-inflammatory cytokines and the markers of cartilage destruction in patients suffering from intra-articular fractures. METHODS We searched Medline, Embase, and Cochrane databases (1960–February 2020) and included studies that were performed on human participants and included control groups. Two investigators assessed the quality of the included studies using Covidence and the Newcastle-Ottawa Scale. RESULTS Based on the surveyed literature, several synovial pro-inflammatory cytokines, including interleukin (IL)-1β, IL-2, IL-6, IL-8, IL-12p70, interferon-y, and tumor necrosis factor-α, were significantly elevated in patients suffering from intra-articular fractures compared to control. A simultaneous elevation of anti-inflammatory cytokines such as IL-10 and IL-1RA was also observed. In contrast, IL-13, CTX-II, and aggrecan concentrations did not differ significantly between the compared cohorts. CONCLUSIONS Overall, intra-articular fractures are associated with an increase in inflammation-related synovial cytokines. However, more standardized studies which focus on the ratio of pro- and anti-inflammatory cytokines at different time points are needed.

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Sudachinoid- and Ichangensin-Type Limonoids from Citrus junos Downregulate Pro-Inflammatory Cytokines

International Journal of Molecular Sciences ◽

10.3390/ijms21186963 ◽

2020 ◽

Vol 21 (18) ◽

pp. 6963

Author(s):

Jihun Shin ◽

Hwa Young Song ◽

Mina Lee

Keyword(s):

Inflammatory Cytokines ◽

Human Colon ◽

Dominant Group ◽

Citrus Junos ◽

Mouse Macrophages ◽

Inflammatory Bowel ◽

Anti Inflammatory ◽

Factor Α ◽

Necrosis Factor ◽

Pro Inflammatory Cytokines

Limonoids, a dominant group of phytochemicals in the Rutaceae family, are known to exhibit several pharmacological activities. To identify natural products having efficacy against inflammatory bowel disease (IBD), we isolated 13 limonoids including a new compound, methyl sudachinoid A, from the seeds of Citrus junos and investigated their anti-inflammatory effects by assessing the expression of pro-inflammatory cytokines in lipopolysaccharide-stimulated RAW 264.7 mouse macrophages and HT-29 human colon epithelial cells. Our findings revealed that limonoids significantly downregulated the pro-inflammatory cytokines, such as interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-α, and nuclear transcription factor κB. In particular, sudachinoid-type compounds, methyl sudachinoid A and sudachinoid B, and ichangensin-type compound, 1-O-methyichangensin downregulated the expression of pro-inflammatory cytokines more potently than other limonoids, nomilin and limonin, which have been previously reported to exhibit anti-inflammatory activities in other cells; nomilin and limonin were therefore employed as positive controls in this study. Herein, we reveal that the anti-inflammatory activities of limonoids including a new compound methyl sudachinoid A from C. junos were mediated via the downregulation of pro-inflammatory cytokines and these limonoids can be employed as potential therapeutic phytochemicals for IBD.

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ANTI-INFLAMMATORY EFFECT OF ELETTARIA CARDAMOM OIL ON CARRAGEENAN-INDUCED PAW EDEMA USING RATS BASED ON TUMOR NECROSIS FACTOR α, INTERLEUKIN 6, AND INTERLEUKIN 1 LEVELS IN SERUM

Asian Journal of Pharmaceutical and Clinical Research ◽

10.22159/ajpcr.2018.v11i2.20434 ◽

2018 ◽

Vol 11 (2) ◽

pp. 207 ◽

Cited By ~ 3

Author(s):

Nithya Sermugapandian ◽

Rubini R ◽

Martina V

Keyword(s):

Tumor Necrosis Factor ◽

Inflammatory Cytokines ◽

Tumor Necrosis ◽

Tumor Necrosis Factor Α ◽

Paw Edema ◽

Anti Inflammatory ◽

Factor Α ◽

Necrosis Factor ◽

Pro Inflammatory Cytokines ◽

Inflammatory Effect

Objective: In this study, we evaluated the anti-inflammatory effect of Elettaria cardamom oil and the underlying mechanism using in vivo models of inflammation.Methods: Male Sprague–Dawley rats, 4-6 weeks old, weighing 120-130 gms are used for the study. The anti-inflammatory study of E. cardamom oil was studied by injecting 0.1 ml of 1% carrageenan to the subplantar region of the right hind paw of rats. The development of acute inflammation was measured at the end of every 1st, 2nd, 3rd, 4th, 5th, and 6th h using plethysmometer.Results: As results from the above study, E. cardamom oil at a dose of 0.175 ml/kg was less significant than that of E. cardamom oil at a dose of 0.280 ml/kg when given orally. A p<0.05 shows a significant decrease in paw edema. It also reduced the levels of pro-inflammatory cytokines such as tumor necrosis factor α, interleukin (IL) 1, and IL 6 levels in the serum. The histopathology results also showed a significant reduction of congested blood vessels with no marked impression for inflammation.Conclusion: E. cardamom oil possesses anti-inflammatory activity in dose-dependent manner as they inhibit the levels of pro-inflammatory cytokines.

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Antidepressant-Like Effect and Mechanism of Action of Honokiol on the Mouse Lipopolysaccharide (LPS) Depression Model

Molecules ◽

10.3390/molecules24112035 ◽

2019 ◽

Vol 24 (11) ◽

pp. 2035 ◽

Cited By ~ 6

Author(s):

Bo Zhang ◽

Ping-Ping Wang ◽

Kai-Li Hu ◽

Li-Na Li ◽

Xue Yu ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Mechanism Of Action ◽

Tail Suspension Test ◽

Interferon Γ ◽

Biologically Active ◽

Free Calcium ◽

Immobility Time ◽

Anti Inflammatory ◽

Factor Α ◽

Pro Inflammatory Cytokines

There is growing evidence that neuroinflammation is closely linked to depression. Honokiol, a biologically active substance extracted from Magnolia officinalis, which is widely used in traditional Chinese medicine, has been shown to exert significant anti-inflammatory effects and improve depression-like behavior caused by inflammation. However, the specific mechanism of action of this activity is still unclear. In this study, the lipopolysaccharide (LPS) mouse model was used to study the effect of honokiol on depression-like behavior induced by LPS in mice and its potential mechanism. A single administration of LPS (1 mg/kg, intraperitoneal injection) increased the immobility time in the forced swimming test (FST) and tail suspension test (TST), without affecting autonomous activity. Pretreatment with honokiol (10 mg/kg, oral administration) for 11 consecutive days significantly improved the immobility time of depressed mice in the FST and TST experiments. Moreover, honokiol ameliorated LPS-induced NF-κB activation in the hippocampus and significantly reduced the levels of the pro-inflammatory cytokines; tumor necrosis factor α (TNF-α), interleukin 1β (IL-1β), and interferon γ (IFN-γ). In addition, honokiol inhibited LPS-induced indoleamine 2,3-dioxygenase (IDO) activation and quinolinic acid (a toxic product) increase and reduced the level of free calcium in brain tissue, thereby inhibiting calcium overload. In summary, our results indicate that the anti-depressant-like effects of honokiol are mediated by its anti-inflammatory effects. Honokiol may inhibit the LPS-induced neuroinflammatory response through the NF-κB signaling pathway, reducing the levels of related pro-inflammatory cytokines, and furthermore, this may affect tryptophan metabolism and increase neuroprotective metabolites.

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Inhibition of SIK2 and SIK3 during differentiation enhances the anti-inflammatory phenotype of macrophages

Biochemical Journal ◽

10.1042/bcj20160646 ◽

2017 ◽

Vol 474 (4) ◽

pp. 521-537 ◽

Cited By ~ 18

Author(s):

Nicola J. Darling ◽

Rachel Toth ◽

J. Simon C. Arthur ◽

Kristopher Clark

Keyword(s):

Inflammatory Cytokines ◽

Drug Targets ◽

Macrophage Polarization ◽

Macrophage Phenotype ◽

Integral Role ◽

Inflammatory Phenotype ◽

Low Levels ◽

Anti Inflammatory ◽

Factor Α ◽

Pro Inflammatory Cytokines

The salt-inducible kinases (SIKs) control a novel molecular switch regulating macrophage polarization. Pharmacological inhibition of the SIKs induces a macrophage phenotype characterized by the secretion of high levels of anti-inflammatory cytokines, including interleukin (IL)-10, and the secretion of very low levels of pro-inflammatory cytokines, such as tumour necrosis factor α. The SIKs, therefore, represent attractive new drug targets for the treatment of macrophage-driven diseases, but which of the three isoforms, SIK1, SIK2 or SIK3, would be appropriate to target remains unknown. To address this question, we developed knock-in (KI) mice for SIK1, SIK2 and SIK3, in which we introduced a mutation that renders the enzymes catalytically inactive. Characterization of primary macrophages from the single and double KI mice established that all three SIK isoforms, and in particular SIK2 and SIK3, contribute to macrophage polarization. Moreover, we discovered that inhibition of SIK2 and SIK3 during macrophage differentiation greatly enhanced the production of IL-10 compared with their inhibition in mature macrophages. Interestingly, macrophages differentiated in the presence of SIK inhibitors, MRT199665 and HG-9-91-01, still produced very large amounts of IL-10, but very low levels of pro-inflammatory cytokines, even after the SIKs had been reactivated by removal of the drugs. Our data highlight an integral role for SIK2 and SIK3 in innate immunity by preventing the differentiation of macrophages into a potent and stable anti-inflammatory phenotype.

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Pro-Inflammatory Cytokines at Ultra-Low Dose Exert Anti-Inflammatory Effect In Vitro: A Possible Mode of Action Involving Sub-Micron Particles?

Dose-Response ◽

10.1177/1559325820961723 ◽

2020 ◽

Vol 18 (4) ◽

pp. 155932582096172

Author(s):

Ilaria Floris ◽

Thorsten Rose ◽

Juan Antonio Collado Rojas ◽

Kurt Appel ◽

Camille Roesch ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Mode Of Action ◽

Inflammatory Diseases ◽

Resistive Pulse ◽

Tnf Α ◽

Anti Inflammatory ◽

Factor Α ◽

Pro Inflammatory Cytokines ◽

Inflammatory Effect

Tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β) are pro-inflammatory cytokines involved in acute and chronic inflammatory diseases. Indeed, immunotherapy blocking these 2 cytokines has been developed. Micro-immunotherapy (MI) also uses ultra-low doses (ULD) of pro-inflammatory cytokines, impregnated on lactose-sucrose pillules, to counteract their overexpression. The study has been conducted with 2 objectives: examine the anti-inflammatory effect in vitro and the capacity of 2 unitary medicines, TNF-α (27 CH) and IL-1β (27 CH), to reduce the secretion of TNF-α in human primary monocytes and THP-1 cells differentiated with phorbol-12-myristate-13-acetate, after lipopolysaccharide (LPS) exposure; then, investigate the presence of particles possibly containing starting materials using tunable resistive pulse sensing technique. The results show that the unitary medicines, tested at 3 pillules concentrations (5.5, 11 and 22 mM), have reduced the secretion of TNF-α in both models by about 10−20% vs. vehicle control, depending on concentration. In this exploratory study, particles (150−1000 nm) have been detected in MI ULD-impregnated pillules and a hypothesis for MI medicines mode of action has been proposed. Conscious that more evaluations are necessary, authors are cautious in the conclusions because the findings described in the study are still limited, and future investigations may lead to different hypothesis.

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Computational Identification of Potential Anti-Inflammatory Natural Compounds Targeting the p38 Mitogen-Activated Protein Kinase (MAPK): Implications for COVID-19-Induced Cytokine Storm

Biomolecules ◽

10.3390/biom11050653 ◽

2021 ◽

Vol 11 (5) ◽

pp. 653

Author(s):

Seth O. Asiedu ◽

Samuel K. Kwofie ◽

Emmanuel Broni ◽

Michael D. Wilson

Keyword(s):

Molecular Docking ◽

P38 Mapk ◽

Inflammatory Cytokines ◽

Binding Energies ◽

Mitogen Activated Protein Kinase ◽

Inflammatory Activity ◽

Computational Techniques ◽

Cytokine Storm ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Severely ill coronavirus disease 2019 (COVID-19) patients show elevated concentrations of pro-inflammatory cytokines, a situation commonly known as a cytokine storm. The p38 MAPK receptor is considered a plausible therapeutic target because of its involvement in the platelet activation processes leading to inflammation. This study aimed to identify potential natural product-derived inhibitory molecules against the p38α MAPK receptor to mitigate the eliciting of pro-inflammatory cytokines using computational techniques. The 3D X-ray structure of the receptor with PDB ID 3ZS5 was energy minimized using GROMACS and used for molecular docking via AutoDock Vina. The molecular docking was validated with an acceptable area under the curve (AUC) of 0.704, which was computed from the receiver operating characteristic (ROC) curve. A compendium of 38,271 natural products originating from Africa and China together with eleven known p38 MAPK inhibitors were screened against the receptor. Four potential lead compounds ZINC1691180, ZINC5519433, ZINC4520996 and ZINC5733756 were identified. The compounds formed strong intermolecular bonds with critical residues Val38, Ala51, Lys53, Thr106, Leu108, Met109 and Phe169. Additionally, they exhibited appreciably low binding energies which were corroborated via molecular mechanics Poisson–Boltzmann surface area (MM-PBSA) calculations. The compounds were also predicted to have plausible pharmacological profiles with insignificant toxicity. The molecules were also predicted to be anti-inflammatory, kinase inhibitors, antiviral, platelet aggregation inhibitors, and immunosuppressive, with probable activity (Pa) greater than probable inactivity (Pi). ZINC5733756 is structurally similar to estradiol with a Tanimoto coefficient value of 0.73, which exhibits anti-inflammatory activity by targeting the activation of Nrf2. Similarly, ZINC1691180 has been reported to elicit anti-inflammatory activity in vitro. The compounds may serve as scaffolds for the design of potential biotherapeutic molecules against the cytokine storm associated with COVID-19.

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Cerebrospinal fluid biomarkers of neuroinflammation in children with hydrocephalus and shunt malfunction

Fluids and Barriers of the CNS ◽

10.1186/s12987-021-00237-4 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Carolyn A. Harris ◽

Diego M. Morales ◽

Rooshan Arshad ◽

James P. McAllister ◽

David D. Limbrick

Keyword(s):

Cerebrospinal Fluid ◽

Inflammatory Cytokines ◽

Protein Concentration ◽

Shunt Revision ◽

Csf Shunt ◽

Shunt Failure ◽

Revision Operation ◽

Protein Levels ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Abstract Background Approximately 30% of cerebrospinal fluid (CSF) shunt systems for hydrocephalus fail within the first year and 98% of all patients will have shunt failure in their lifetime. Obstruction remains the most common reason for shunt failure. Previous evidence suggests elevated pro-inflammatory cytokines in CSF are associated with worsening clinical outcomes in neuroinflammatory diseases. The aim of this study was to determine whether cytokines and matrix metalloproteinases (MMPs) contribute towards shunt failure in hydrocephalus. Methods Using multiplex ELISA, this study examined shunt failure through the CSF protein concentration profiles of select pro-inflammatory and anti-inflammatory cytokines, as well as select MMPs. Interdependencies such as the past number of previous revisions, length of time implanted, patient age, and obstruction or non-obstruction revision were examined. The pro-inflammatory cytokines were IL-1β, IL-2, IL-5, IL-6, IL-8, IL-12, IL-17, TNF-α, GM-CSF, IFN-γ. The anti-inflammatory cytokines were IL-4 and IL-10, and the MMPs were MMP-2, MMP-3, MMP-7, MMP-9. Protein concentration is reported as pg/mL for each analyte. Results Patient CSF was obtained at the time of shunt revision operation; all pediatric (< 18), totaling n = 38. IL-10, IL-6, IL-8 and MMP-7 demonstrated significantly increased concentrations in patient CSF for the non-obstructed subgroup. Etiological examination revealed IL-6 was increased in both obstructed and non-obstructed cases for PHH and congenital hydrocephalic patients, while IL-8 was higher only in PHH patients. In terms of number of past revisions, IL-10, IL-6, IL-8, MMP-7 and MMP-9 progressively increased from zero to two past revisions and then remained low for subsequent revisions. This presentation was notably absent in the obstruction subgroup. Shunts implanted for three months or less showed significantly increased concentrations of IL-6, IL-8, and MMP-7 in the obstruction subgroup. Lastly, only patients aged six months or less presented with significantly increased concentration of IL-8 and MMP-7. Conclusion Non-obstructive cases are reported here to accompany significantly higher CSF cytokine and MMP protein levels compared to obstructive cases for IL-10, IL-6, IL-8, MMP-7 and MMP-9. A closer examination of the definition of obstruction and the role neuroinflammation plays in creating shunt obstruction in hydrocephalic patients is suggested.

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Role of Inflammatory Cytokines in COVID-19 Patients: A Review on Molecular Mechanisms, Immune Functions, Immunopathology and Immunomodulatory Drugs to Counter Cytokine Storm

Vaccines ◽

10.3390/vaccines9050436 ◽

2021 ◽

Vol 9 (5) ◽

pp. 436

Author(s):

Ali A. Rabaan ◽

Shamsah H. Al-Ahmed ◽

Javed Muhammad ◽

Amjad Khan ◽

Anupam A Sule ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Inflammatory Markers ◽

Therapeutic Drug ◽

Molecular Pathways ◽

Cytokine Storm ◽

Immunomodulatory Drugs ◽

Alveolar Cells ◽

Systemic Complications ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a severe pandemic of the current century. The vicious tentacles of the disease have been disseminated worldwide with unknown complications and repercussions. Advanced COVID-19 syndrome is characterized by the uncontrolled and elevated release of pro-inflammatory cytokines and suppressed immunity, leading to the cytokine storm. The uncontrolled and dysregulated secretion of inflammatory and pro-inflammatory cytokines is positively associated with the severity of the viral infection and mortality rate. The secretion of various pro-inflammatory cytokines such as TNF-α, IL-1, and IL-6 leads to a hyperinflammatory response by recruiting macrophages, T and B cells in the lung alveolar cells. Moreover, it has been hypothesized that immune cells such as macrophages recruit inflammatory monocytes in the alveolar cells and allow the production of large amounts of cytokines in the alveoli, leading to a hyperinflammatory response in severely ill patients with COVID-19. This cascade of events may lead to multiple organ failure, acute respiratory distress, or pneumonia. Although the disease has a higher survival rate than other chronic diseases, the incidence of complications in the geriatric population are considerably high, with more systemic complications. This review sheds light on the pivotal roles played by various inflammatory markers in COVID-19-related complications. Different molecular pathways, such as the activation of JAK and JAK/STAT signaling are crucial in the progression of cytokine storm; hence, various mechanisms, immunological pathways, and functions of cytokines and other inflammatory markers have been discussed. A thorough understanding of cytokines’ molecular pathways and their activation procedures will add more insight into understanding immunopathology and designing appropriate drugs, therapies, and control measures to counter COVID-19. Recently, anti-inflammatory drugs and several antiviral drugs have been reported as effective therapeutic drug candidates to control hypercytokinemia or cytokine storm. Hence, the present review also discussed prospective anti-inflammatory and relevant immunomodulatory drugs currently in various trial phases and their possible implications.

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Human umbilical cord mesenchymal stem cell-derived extracellular vesicles attenuate experimental autoimmune encephalomyelitis via regulating pro and anti-inflammatory cytokines

Scientific Reports ◽

10.1038/s41598-021-91291-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Samira Ahmadvand Koohsari ◽

Abdorrahim Absalan ◽

Davood Azadi

Keyword(s):

Spinal Cord ◽

Body Weight ◽

Extracellular Vesicles ◽

Inflammatory Cytokines ◽

Clinical Score ◽

Human Umbilical Cord ◽

Therapeutic Effects ◽

Leukocyte Infiltration ◽

Anti Inflammatory ◽

Pro Inflammatory Cytokines

AbstractThe therapeutic effects of mesenchymal stem cells-extracellular vesicles have been proved in many inflammatory animal models. In the current study, we aimed to investigate the effect of extracellular vesicles (EVs) derived from human umbilical cord-MSC (hUCSC-EV) on the clinical score and inflammatory/anti-inflammatory cytokines on the EAE mouse model. After induction of EAE in C57Bl/6 mice, they were treated intravenously with hUCSC-EV or vehicle. The clinical score and body weight of all mice was registered every day. On day 30, mice were sacrificed and splenocytes were isolated for cytokine assay by ELISA. Cytokine expression of pro-/anti-inflammatory cytokine by real-time PCR, leukocyte infiltration by hematoxylin and eosin (H&E) staining, and the percent of glial fibrillary acidic protein (GFAP) and myelin basic protein (MBP) positive cells by immunohistochemistry were assessed in the spinal cord. Our results showed that hUCSC-EV-treated mice have lower maximum mean clinical score (MMCS), pro-inflammatory cytokines, and inflammatory score in comparison to the control mice. We also showed that hUCSC-EV administration significantly improved body weight and increased the anti-inflammatory cytokines and the frequency of Treg cells in the spleen. There was no significant difference in the percent of GFAP and MBP positive cells in the spinal cord of experimental groups. Finally, we suggest that intravenous administration of hUCSC-EV alleviate induce-EAE by reducing the pro-inflammatory cytokines, such as IL-17a, TNF-α, and IFN-γ, and increasing the anti-inflammatory cytokines, IL-4 and IL-10, and also decrease the leukocyte infiltration in a model of MS. It seems that EVs from hUC-MSCs have the same therapeutic effects similar to EVs from other sources of MSCs, such as adipose or bone marrow MSCs.

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